Role of toll-like receptor 4 and sex in 6-hydroxydopamine–induced behavioral impairments and neurodegeneration in mice. (December 2021)

• Record Type: Journal Article
• Authors: Somensi, Nauana; Lopes, Samantha Cristiane; Gasparotto, Juciano; Mayer Gonçalves, Rosângela; Tiefensee-Ribeiro, Camila; Oppermann Peixoto, Daniel; Ozorio Brum, Pedro; Pinho, Cibele Martins; Agnes, Jonathan Paulo; Santos, Lucas; de Oliveira, Jade; Spiller, Fernando; Fonseca Moreira, José Cláudio; Zanotto-Filho, Alfeu; Prediger, Rui Daniel; Pens Gelain, Daniel
• Is Part Of: Neurochemistry international. Volume 151(2021)
• Publication Date: 2021-12
• Subjects: Parkinson's disease -- 6-Hydroxydopamine -- Motor function -- Toll-like receptor 4 -- Microglia -- Neuroinflammation; 6-OHDA 6-hydroxydopamine -- CNS central nervous system -- CX cortex -- DA dopamine -- DAMPs damage-associated molecular patterns -- DAT dopamine transporter -- IF immunofluorescence -- L-DOPA levodopa -- PD Parkinson's disease -- PFA paraformaldehyde -- RAGE receptor for advanced glycation end-products -- RR rotarod -- SN substantia nigra -- SNc substantia nigra pars compacta -- ST striatum -- TLR4 Toll-like receptor 4 -- TLR4−/− TLR4 gene knockout -- VTA ventral tegmental area -- WT wild-type; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2021.105215
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of the nigrostriatal dopaminergic neurons that are associated with motor alterations and non-motor manifestations (such as depression). Neuroinflammation is a process with a critical role in the pathogenesis of PD. In this regard, toll-like receptor 4 (TLR4) is a central mediator of immune response in PD. Moreover, there are gender-related differences in the incidence, prevalence, and clinical features of PD. Therefore, we aimed to elucidate the role of TLR4 in the sex-dependent response to dopaminergic denervation induced by 6-hydroxydopamine (6-OHDA) in mice. Female and male adult wildtype (WT) and TLR4 knockout ( TLR4 −/− ) mice were administered with unilateral injection of 6-OHDA in the dorsal striatum, and non-motor and motor impairments were evaluated for 30 days, followed by biochemistry analysis in the substantia nigra pars compacta (SNc), dorsal striatum, and dorsoventral cortex. Early non-motor impairments (i.e., depressive-like behavior and spatial learning deficits) induced by 6-OHDA were observed in the male WT mice but not in male TLR4 −/− or female mice. Motor alterations were observed after administration of 6-OHDA in both strains, and the lack of TLR4 was also related to motor commitment. Moreover, ablation of TLR4 prevented 6-OHDA–induced dopaminergic denervation and microgliosis in the SNc, selectively in female mice. These results reinforced the existence of sex-biased alterations in PD and indicated TLR4 as a promising therapeutic target for the motor and non-motor symptoms of PD, which will help counteract the neuroinflammatory and neurodegenerative processes. Graphical abstract: Image 1 Highlights: "TLR4 regulates early depressive-like behaviors induced by 6-OHDA in male mice". "Females have late behavior effects and more robust immune response to 6-OHDA". "6-OHDA-induced DA denervation and glial reactivity is prevented by TLR4−/− in females". "TLR4 modulates neuroinflammation in gender-specific manner.".